Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA

Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2011; 108(7):3047-52. DOI: 10.1073/pnas.1010529108
Source: PubMed

ABSTRACT Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.

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    • "In recent years, crosskingdom investigations have garnered attention, especially on the symbiotic bacteria in animals. The intestinal microbiota can play crucial roles in digestion, nutrition, and immune response of the animal hosts including human (Harris 1993; Turnbaugh et al. 2006; Renz et al. 2011) or during development , such as of the mammalian brain (Diaz Heijtz et al. 2011) and vertebrate gastrointestinal tract (Bouskra et al. 2008). In a recent study, Moran and Yun (2015) found that the pea aphid Acyrthosiphon pisum with the bacterium Buchnera increased in heat tolerance, demonstrating that the symbiont genotype can also affect the host ecology and, thus, its evolutionary history. "
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    ABSTRACT: During evolution of animals, their co-evolution with bacteria has generally been ignored. Recent studies have provided evidences that the symbiotic bacteria in the animal gut can either be essential or contributing to the plasticity of the host. The Crustacea includes crab, crayfish, lobster, and shrimp and represents the second largest subphylum on the planet. Although there are already studies investigating the intestinal bacterial communities in crustaceans, none of them has examined the microbiota in different parts of the digestive system during the gonad development of the host. Here, we utilized a new shrimp model Neocaridina denticulata and sequenced the 16S rRNA using the Ion Torrent platform to survey the bacterial populations colonizing the hepatopancreas, foregut, and intestine, including midgut and hindgut, of the early, mid, and late ovarian maturation stages of the shrimp. The predominant bacteria phylum was found to be Proteobacteria, with more than 80 % reads from the gut flora at the early gonad development belonged to a Coxiella-type bacterium. Distinct bacterial communities can be detected between the hepatopancreas and gut, although no significant difference could be revealed between the different regions of the gut investigated. Surprisingly, during the gonad development, bacterial diversity changed rapidly in the gut but not the hepatopancreas. This study provides the first evidence that microbiota modified differentially in specific regions of the digestive tract during gonadal development of crustaceans.
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    • "Immun. (2015), behavior, suggesting that gut microbes impact anxiety-like behavior (Diaz Heijtz et al., 2011; Neufeld et al., 2011). More recently, the effects of exogenous probiotic microbes, such as bacteria in the genus Bifidobacterium or Lactobacillus, have been shown to attenuate anxiety in both laboratory animals and human participants (Messaoudi et al., 2011a), thus reinforcing the notion that gut microbes can impact behavior. "
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    ABSTRACT: There are extensive bidirectional interactions between the gut microbiota and the central nervous system (CNS), and studies demonstrate that stressor exposure significantly alters gut microbiota community structure. We tested whether oligosaccharides naturally found in high levels in human milk, which have been reported to impact brain development and enhance the growth of beneficial commensal microbes, would prevent stressor-induced alterations in gut microbial community composition and attenuate stressor-induced anxiety-like behavior. Mice were fed standard laboratory diet, or laboratory diet containing the human milk oligosaccharides 3'Sialyllactose (3'SL) or 6'Sialyllactose (6'SL) for 2weeks prior to being exposed to either a social disruption stressor or a non-stressed control condition. Stressor exposure significantly changed the structure of the colonic mucosa-associated microbiota in control mice, as indicated by changes in beta diversity. The stressor resulted in anxiety-like behavior in both the light/dark preference and open field tests in control mice. This effect was associated with a reduction in immature neurons in the dentate gyrus as indicated by doublecortin (DCX) immunostaining. These effects were not evident in mice fed milk oligosaccharides; stressor exposure did not significantly change microbial community structure in mice fed 3'SL or 6'SL. In addition, 3'SL and 6'SL helped maintain normal behavior on tests of anxiety-like behavior and normal numbers of DCX+ immature neurons. These studies indicate that milk oligosaccharides support normal microbial communities and behavioral responses during stressor exposure, potentially through effects on the gut microbiota-brain axis. Copyright © 2015. Published by Elsevier Inc.
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    • "Recent excitement in the field has been generated from findings implicating the microbial community in a variety of dysbioses from gut associated diseases like obesity and malnutrition (Turnbaugh et al., 2006; Smith et al., 2013), inflammatory bowel disease (Hold, 2014), and celiac disease (Nistal et al., 2012) to neurological disorders like depression (Park et al., 2013), anxiety (Diaz Heijtz et al., 2011), and autism (Hsiao et al., 2013). While significant contributions have been made to understand developed microbial communities in healthy and diseased adults, large gaps remain in understanding the acquisition of the human microbiome at birth, especially among preterm infants (Groer et al., 2014). "
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    ABSTRACT: While there has been growing interest in the gut microbiome in recent years, it remains unclear whether closely related species and strains have similar or distinct functional roles and if organisms capable of both aerobic and anaerobic growth do so simultaneously. To investigate these questions, we implemented a high-throughput mass spectrometry-based proteomics approach to identify proteins in fecal samples collected on days of life 13-21 from an infant born at 28 weeks gestation. No prior studies have coupled strain-resolved community metagenomics to proteomics for such a purpose. Sequences were manually curated to resolve the genomes of two strains of Citrobacter that were present during the later stage of colonization. Proteome extracts from fecal samples were processed via a nano-2D-LC-MS/MS and peptides were identified based on information predicted from the genome sequences for the dominant organisms, Serratia and the two Citrobacter strains. These organisms are facultative anaerobes, and proteomic information indicates the utilization of both aerobic and anaerobic metabolisms throughout the time series. This may indicate growth in distinct niches within the gastrointestinal tract. We uncovered differences in the physiology of coexisting Citrobacter strains, including differences in motility and chemotaxis functions. Additionally, for both Citrobacter strains we resolved a community-essential role in vitamin metabolism and a predominant role in propionate production. Finally, in this case study we detected differences between genome abundance and activity levels for the dominant populations. This underlines the value in layering proteomic information over genetic potential.
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